EP0657462B1 - Substituted phosphonic acids - Google Patents

Substituted phosphonic acids Download PDF

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Publication number
EP0657462B1
EP0657462B1 EP94119095A EP94119095A EP0657462B1 EP 0657462 B1 EP0657462 B1 EP 0657462B1 EP 94119095 A EP94119095 A EP 94119095A EP 94119095 A EP94119095 A EP 94119095A EP 0657462 B1 EP0657462 B1 EP 0657462B1
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Prior art keywords
organic amine
reaction
reaction mixture
lactam
phosphorous acid
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German (de)
French (fr)
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EP0657462A1 (en
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Michael Bamber
Gary Woodward
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Solvay Solutions UK Ltd
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Albright and Wilson UK Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/5532—Seven-(or more) membered rings

Definitions

  • This invention relates to an improved method for the production of acids and to azacycloalkane-2,2-diphosphonic azacycloalkane-2,2-diphosphonic acids obtained thereby.
  • the present invention will be described herein with particular reference to azacycloheptane-2,2-diphosphonic acid and to azacyclononane-2,2-diphosphonic acid, although it is not to be construed as being limited thereto.
  • azacycloalkane-2,2-diphosphonic acid denotes a compound of the general formula where n is a whole number of from 2 to 16 and Y is H, an alkyl or alkenyl, a substituted alkyl or an aryl group, such that the group "Y" remains unchanged during the reaction.
  • AHP azacycloheptane-2,2-diphosphonic acid
  • US-A-3941772, DE-A-2541981 and DE-A-3808074 The preparation of other azacycloalkane-2,2-diphosphonic acids, has been described in DE-A-4114586. All of these prior dents suggest that the use of toxic and/or expensive solvents (e.g. chlorobenzene, dioxane, and glycols) are essential in order to prevent the reaction mixture from becoming unstirrable and/or the reaction itself becoming unreproducible, and/or uneconomical due to the low yields of product obtained.
  • toxic and/or expensive solvents e.g. chlorobenzene, dioxane, and glycols
  • an organic amine and/or amine salt e.g. an amine hydrochloride, amine hydrobromide or an amine salt of phosphorous acid
  • a reaction mixture including a lactam, a phosphorus trihalide, phosphorous acid and/or water, followed by hydrolysis and subsequent purification of the product, leads to the production of the corresponding azacycloalkane-2,2-diphosphonic acid, in good yield, with the reaction mixture remaining stirrable throughout the reaction.
  • the present invention provides a method for the production of azacycloalkane-2,2-diphosphonic acids of general formula; where n is a whole number of from 2 to 16 and Y is H, an alkyl or alkenyl, a substituted alkyl, or an aryl, such that the group "Y" remains unchanged during the reaction, by the reaction of a lactam with a phosphorus trihalide, in the presence of phosphorous acid and/or water, in which the reaction mixture also includes an organic amine and/or an organic amine salt, followed by hydrolysis of the reaction mixture and purification of the reaction product to obtain the diphosphonic acid.
  • the present invention also provides azacycloalkane-2,2-diphosphonic acids produced by the method described in the immediately-preceding paragraph.
  • the lactam may be, for example, caprolactam, whereby the acid produced is azacycloheptane-2,2-diphosphonic acid, or the lactam may be, for example, 2-azacyclononanone, whereby the acid produced is azacyclononane-2,2-diphosphonic acid.
  • the phosphorus trihalide is suitably phosphorus trichloride or phosphorus tribromide.
  • the organic amine is a tertiary amine and the organic amine salt is a tertiary amine phosphorous acid salt, hydrochloride, or hydrobromide.
  • Suitable amines and amine salts include triethylamine, tributylamine and their phosphorous acid salts hydrochlorides, or hydrobromides.
  • the organic amine phosphorous acid salt may be formed in situ during the reaction.
  • the ratio of amine or amine salt to lactam in the reaction mixture is preferably about 1:1 molar, but may be in the range 0.1:1 to 4:1 molar, for example 0.1:1 to 2:1 molar, especially 0.5:1 to 2:1 molar.
  • Azacycloalkane-2,2-diposphonic acids are known to exhibit excellent sequestering properties for polyvalent metal ions, especially di-and tri-valent metal ions, and AHP is known to be particularly suitable for use in toothpastes, toothpolishes and mouthwash formulations.
  • the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried. Yield of AHP was 156g, 60% of theoretical yield.
  • the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried. Yield of AHP was 53g, 41% of theoretical yield.
  • triethylamine 51g, 0.5m
  • caprolactam 57g, 0.5m
  • phosphorus trichloride 151g, 1.1m
  • the reaction mixture was then heated over 120 minutes to 90°C and held at this temperature for a further 30 minutes. During the total reaction time the reaction mixture was stirrable and no foaming took place.
  • the mixture was hydrolysed at 60°C with 200g of water then heated to reflux and held for 60 minutes. During this process the pale orange product precipitated and was isolated by filtration.
  • triethylamine 51g, 0.5m
  • caprolactam 57g, 0.5m
  • phosphorus trichloride 151g, 1.1m
  • the reaction mixture was then heated over 120 minutes to 110°C and held at this temperature for a further 30 minutes. During the total reaction time the reaction mixture was stirrable and no foaming took place.
  • the mixture was hydrolysed at 60°C with 200g of water then heated to reflux and held for 60 minutes. During this process the pale orange product precipitated and was isolated by filtration.
  • the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried. Yield of AHP was 63g, 49% of theoretical yield.
  • the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried. Yield of AHP was 162g, 63% of theoretical yield.
  • reaction mixture was then cooled to room temperature during which the reaction product crystallised out of the mixture, and was then isolated by filtration. To further purify the crude product it was firstly washed with water (approximately 200ml) followed by washing with acetone (approximately 200ml). Finally the product was vacuum dried.
  • the product was an off white/orange solid, identified by 31 P and 13 C NMR spectroscopy as azacyclononane-2,2-diphosphonic acid.
  • the reaction mixture was then hydrolysed by the addition over 40 minutes of the reaction mixture to water (900 kg).
  • the crude product was an orange solid which was then isolated by filtration, slurried with water, adjusted with sodium hydroxide to pH 9.3 and then filtered.
  • the filtrate was reacidified with concentrated hydrochloride acid to pH 0.9. A white solid was precipitated during this acidification stage. To further purify the product it was filtered, washed with water and vacuum dried. Yield of azacycloheptane-2,2-diphosphonic acid was 442 kg, 45% of theorectical yield.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

A method for the production of azacycloalkane-2,2-diphosphonic acids of general formula; <CHEM> where n is a whole number of from 2 to 16, Y is H, an alkyl or alkenyl, a substituted alkyl, or an aryl, such that the group "Y" remains unchanged during the reaction, by reaction of a lactam with a phosphorus trihalide in the presence of phosphorous acid and/or water, in which the reaction mixture also includes an organic amine and/or or an organic amine salt, said reaction being followed by hydrolysis of the reaction mixture and purification of the reaction product to obtain the diphosphonic acid. The method is exemplified by the preparation of azacycloheptane-2,2-diphosphonic acid, and azacyclononane-2,2-diphosphonic acid.

Description

This invention relates to an improved method for the production of acids and to azacycloalkane-2,2-diphosphonic azacycloalkane-2,2-diphosphonic acids obtained thereby. The present invention will be described herein with particular reference to azacycloheptane-2,2-diphosphonic acid and to azacyclononane-2,2-diphosphonic acid, although it is not to be construed as being limited thereto.
Throughout this description, the term "azacycloalkane-2,2-diphosphonic acid" denotes a compound of the general formula
Figure 00010001
where n is a whole number of from 2 to 16 and Y is H, an alkyl or alkenyl, a substituted alkyl or an aryl group, such that the group "Y" remains unchanged during the reaction.
The preparation of azacycloheptane-2,2-diphosphonic acid (hereinafter AHP) has been described in US-A-3941772, DE-A-2541981 and DE-A-3808074. The preparation of other azacycloalkane-2,2-diphosphonic acids, has been described in DE-A-4114586. All of these prior dents suggest that the use of toxic and/or expensive solvents (e.g. chlorobenzene, dioxane, and glycols) are essential in order to prevent the reaction mixture from becoming unstirrable and/or the reaction itself becoming unreproducible, and/or uneconomical due to the low yields of product obtained.
It has now been discovered that the addition of an organic amine and/or amine salt (e.g. an amine hydrochloride, amine hydrobromide or an amine salt of phosphorous acid) to a reaction mixture including a lactam, a phosphorus trihalide, phosphorous acid and/or water, followed by hydrolysis and subsequent purification of the product, leads to the production of the corresponding azacycloalkane-2,2-diphosphonic acid, in good yield, with the reaction mixture remaining stirrable throughout the reaction.
Accordingly, the present invention provides a method for the production of azacycloalkane-2,2-diphosphonic acids of general formula;
Figure 00020001
where n is a whole number of from 2 to 16 and Y is H, an alkyl or alkenyl, a substituted alkyl, or an aryl, such that the group "Y" remains unchanged during the reaction, by the reaction of a lactam with a phosphorus trihalide, in the presence of phosphorous acid and/or water, in which the reaction mixture also includes an organic amine and/or an organic amine salt, followed by hydrolysis of the reaction mixture and purification of the reaction product to obtain the diphosphonic acid.
The present invention also provides azacycloalkane-2,2-diphosphonic acids produced by the method described in the immediately-preceding paragraph.
The lactam may be, for example, caprolactam, whereby the acid produced is azacycloheptane-2,2-diphosphonic acid, or the lactam may be, for example, 2-azacyclononanone, whereby the acid produced is azacyclononane-2,2-diphosphonic acid.
The phosphorus trihalide is suitably phosphorus trichloride or phosphorus tribromide.
Preferably, the organic amine is a tertiary amine and the organic amine salt is a tertiary amine phosphorous acid salt, hydrochloride, or hydrobromide. Suitable amines and amine salts include triethylamine, tributylamine and their phosphorous acid salts hydrochlorides, or hydrobromides. The organic amine phosphorous acid salt may be formed in situ during the reaction.
The ratio of amine or amine salt to lactam in the reaction mixture is preferably about 1:1 molar, but may be in the range 0.1:1 to 4:1 molar, for example 0.1:1 to 2:1 molar, especially 0.5:1 to 2:1 molar.
Azacycloalkane-2,2-diposphonic acids are known to exhibit excellent sequestering properties for polyvalent metal ions, especially di-and tri-valent metal ions, and AHP is known to be particularly suitable for use in toothpastes, toothpolishes and mouthwash formulations.
The present invention will be further illustrated by way of the following Examples:-
Example 1 - Preparation of AHP
Into a stirred mixture of caprolactam (113g, 1.0m), triethylamine hydrochloride (138g, 1.0m) and water (60g, 3.36m), was added phosphorus trichloride (292g, 2.12m) over 40 minutes and at a temperature below 40°C.The reaction mixture was then heated over 120 minutes to 80°C and held at this temperature for a further 120 minutes. During the total reaction time the reaction mixture was stirrable and no foaming took place. The mixture was hydrolysed at 80°C with 400ml of 20% hydrochloric acid then heated to reflux and held for 240 minutes. During this process the pale orange product precipitated and was isolated by filtration. For further purification, the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried.
Yield of AHP was 156g, 60% of theoretical yield.
Example 2 - Preparation of AHP
Into a stirred mixture of caprolactam (57g, 0.5m) tributylamine hydrochloride (89g, 0.4m) and water (30g, 1.65m), was added phosphorus trichloride (151g, 1.1m) over 40 minutes and at a temperature below 40°C. The reaction mixture was then heated over 120 minutes to 90°C and held at this temperature for a further 30 minutes. During the total reaction time the reaction mixture was stirrable and no foaming took place. The mixture was hydrolysed at 80°C with 250ml of 20% hydrochloric acid then heated to reflux and held for 180 minutes. During this process the pale orange product precipitated and was isolated by filtration. For further purification, the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried.
Yield of AHP was 53g, 41% of theoretical yield.
Example 3 - Preparation of AHP
Into stirred and cooled triethylamine (51g, 0.5m) was added 54g of concentrated hydrochloric acid followed by caprolactam (57g, 0.5m). To this solution was added phosphorus trichloride (151g, 1.1m) over 40 minutes and at a temperature below 50°C. The reaction mixture was then heated over 120 minutes to 90°C and held at this temperature for a further 30 minutes. During the total reaction time the reaction mixture was stirrable and no foaming took place. The mixture was hydrolysed at 60°C with 200g of water then heated to reflux and held for 60 minutes. During this process the pale orange product precipitated and was isolated by filtration. For further purification the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried.
Yield of AHP was 78g, 60% of theoretical yield.
Example 4 - Preparation of AHP
Into stirred and cooled triethylamine (51g, 0.5m) was added 54g of concentrated hydrochloric acid followed by caprolactam (57g, 0.5m). To this solution was added phosphorus trichloride (151g, 1.1m) over 40 minutes and at a temperature below 50°C. The reaction mixture was then heated over 120 minutes to 110°C and held at this temperature for a further 30 minutes. During the total reaction time the reaction mixture was stirrable and no foaming took place. The mixture was hydrolysed at 60°C with 200g of water then heated to reflux and held for 60 minutes. During this process the pale orange product precipitated and was isolated by filtration. For further purification, the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried.
Yield of AHP was 63g, 49% of theoretical yield.
Example 5 - Preparation of AHP
Into a stirred mixture of caprolactam (113g, 1.0m), triethylamine hydrochloride (138g, 1.0m) and water (60g, 3.36m) was added phosphorus trichloride (292g, 2.12m) over 40 minutes and at a temperature below 40°C. The reaction mixture was then heated over 120 minutes to 80°C and held at this temperature for a further 240 minutes. During the total reaction time the reaction mixture was stirrable and no foaming took place. The reaction mixture was added to 400ml of 20% hydrochloric acid (which was preheated to 60°C) then heated to reflux and held for 120 minutes. During this process the pale orange product precipitated and was isolated by filtration. For further purification, the crude product was suspended in water, adjusted to a pH value of 9 with sodium hydroxide solution, and the undissolved polymer product separated. After the acidification of the salt solution with concentrated hydrochloric acid to pH 1, the product was separated by filtration and vacuum dried.
Yield of AHP was 162g, 63% of theoretical yield.
Example 6 - Preparation of azacyclononane-2,2-diphosphonic acid
Into a stirred mixture of 2-azacyclononanone (30g, 0.213M), triethylamine hydrochloride (29.2g, 0.212M) and water (12.6g, 0.7M), was added phosphorous trichloride (61.8g, 0.213M) dropwise, with the addition rate adjusted to maintain the reaction mixture below 40°C. The reaction mixture was then heated over 60 minutes to 80°C and held at this temperature for a further 150 minutes. During the total reaction time the reaction mixture was stirrable, becoming orange and opaque in appearance, although remaining homogeneous. The reaction mixture was then hydrolysed at approximately 70°C by slowly adding water (200ml), then heated to reflux and held at 85°C for 60 minutes. The reaction mixture was then cooled to room temperature during which the reaction product crystallised out of the mixture, and was then isolated by filtration. To further purify the crude product it was firstly washed with water (approximately 200ml) followed by washing with acetone (approximately 200ml). Finally the product was vacuum dried.
The product was an off white/orange solid, identified by 31P and 13C NMR spectroscopy as azacyclononane-2,2-diphosphonic acid.
Yield of azacyclononane-2,2-diphosphonic acid was 28g, 46% of theoretical yield.
Example 7 - preparation of AHP
Into a stirred mixture of phosphorous acid flake (108.5kg) and concentrated hydrochloric acid (245 kg, 36% w/w) was addded triethylamine (225 kg) over 2 hours. Caprolactam (287 kg) was then added, with phosphorous trichloride (702 kg) added over a 9½ hour period, with the addition rate adjusted to maintain the reaction mixture below 65°C. When the reaction was complete, the reaction mixture was then held at 53-57°C for 1 hour, and was then heated over 1½ hours to 85°C and held at this temperature for a further 7.3 hours. During the total reaction time the reaction mixture was stirrable, with an orange mixture formed at the end of the reaction time. The reaction mixture was then hydrolysed by the addition over 40 minutes of the reaction mixture to water (900 kg). The crude product was an orange solid which was then isolated by filtration, slurried with water, adjusted with sodium hydroxide to pH 9.3 and then filtered. The filtrate was reacidified with concentrated hydrochloride acid to pH 0.9. A white solid was precipitated during this acidification stage. To further purify the product it was filtered, washed with water and vacuum dried.
Yield of azacycloheptane-2,2-diphosphonic acid was 442 kg, 45% of theorectical yield.

Claims (8)

  1. A method for the production of azacyclo diphosphonic acids, characterised by the reaction of a lactam with a phosphorus trihalide in the presence of phosphorous acid and/or water, followed by hydrolysis of the reaction mixture and purification of the reaction product, and further characterised in that the reaction mixture also includes an organic amine and/or an organic amine salt, whereby the diphosphonic acid has the general formula;
    Figure 00080001
    wherein n is a whole number in the range 2 to 16 and Y is H, an alkyl or alkenyl, a substituted alkyl or aryl, such that the group "Y" remains unchanged during the reaction.
  2. A method according to Claim 1, characterised in that n is a whole number in the range 3 to 9.
  3. A method according to Claim 1, characterised in that the lactam is caprolactam.
  4. A method according to Claim 1 or 2, characterised in that the lactam is 2-azacyclononanone.
  5. A method according to any one of Claims 1 to 4, characterised in that the phosphorus trihalide is phosphorus trichloride or phosphorus tribromide.
  6. A method according to any one of Claims 1 to 5, characterised in that the organic amine is a tertiary amine, for example triethylamine or tributylamine.
  7. A method according to any one of Claims 1 to 5 characterised in that the organic amine salt is an organic amine hydrochloride, organic amine hydrobromide or organic amine phosphorous acid salt for example a tertiary amine hydrochloride, hydrobromide or phosphorous acid salt, preferably triethylamine hydrochloride, hydrobromide or phosphorous acid salt, tributylamine hydrochloride, hydrobromide or phosphorous acid salt.
  8. A method according to any one of Claims 1 to 7, characterised in that the ratio of organic amine or organic amine salt to lactam in the reaction mixture is in the range 0.1:1 to 4:1 molar, for example 0.1:1 to 2:1 molar, preferably 0.5:1 to 2:1 molar, especially about 1:1 molar.
EP94119095A 1993-12-08 1994-12-03 Substituted phosphonic acids Expired - Lifetime EP0657462B1 (en)

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GB9325113 1993-12-08
GB939325113A GB9325113D0 (en) 1993-12-08 1993-12-08 Substituted phosphonic acids

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EP0657462B1 true EP0657462B1 (en) 1999-01-07

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JP (1) JPH07196677A (en)
AT (1) ATE175416T1 (en)
CA (1) CA2137490A1 (en)
DE (1) DE69415784T2 (en)
ES (1) ES2127876T3 (en)
GB (2) GB9325113D0 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1188761A1 (en) * 2000-09-18 2002-03-20 SOLVAY (Société Anonyme) Novel geminal-diphosphonic acids and their manufacture
GB0115824D0 (en) * 2001-06-28 2001-08-22 Rhodia Cons Spec Ltd Improved solvent systems

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE121644C (en) *
DE2003141A1 (en) * 1970-01-24 1971-07-29 Bayer Ag 2-Oxo-dihydroquinoline thionophosphorus (phosphonic) acid esters and process for their preparation
DE2343196C3 (en) * 1973-08-27 1980-01-10 Henkel Kgaa, 4000 Duesseldorf Aiacycloalkan-2 ^ -diphosphonic acids or their water-soluble salts
DE2541981A1 (en) * 1975-09-20 1977-03-24 Bayer Ag Azacycloalkane diphosphonic acid metal sequestrants - made by reacting lactams with phosphorus trihalide in the presence of specified quantities of water
DE3808074A1 (en) * 1988-03-11 1989-09-21 Henkel Kgaa METHOD FOR PRODUCING AZACYCLOALKANE-2,2-DIPHOSPHONIC ACIDS
DE4114586A1 (en) * 1991-05-04 1992-11-05 Boehringer Mannheim Gmbh MEDICINAL PRODUCTS CONTAINING AZACYCLODIPHOSPHONIC ACID DERIVATIVES, NEW AZACYCLODIPHOSPHONIC ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF

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ATE175416T1 (en) 1999-01-15
US5659035A (en) 1997-08-19
GB2284604B (en) 1997-08-20
DE69415784D1 (en) 1999-02-18
DE69415784T2 (en) 1999-06-24
GB9424356D0 (en) 1995-01-18
CA2137490A1 (en) 1995-06-09
ES2127876T3 (en) 1999-05-01
JPH07196677A (en) 1995-08-01
EP0657462A1 (en) 1995-06-14
GB9325113D0 (en) 1994-02-09
GB2284604A (en) 1995-06-14

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